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(Circulation. 1999;99:468-471.)
© 1999 American Heart Association, Inc.

Editorials

Appreciating -Adrenergic Receptors and Their Role in Ischemic Left Ventricular Dysfunction

Morton J. Kern, MD

From the Department of Internal Medicine, Division of Cardiology, Saint Louis University Hospital, St Louis, Mo.

Correspondence to Morton J. Kern, MD, Director, J.G. Mudd Cardiac Catheterization Laboratory, Saint Louis University Hospital, 3635 Vista Ave at Grand Blvd, St Louis, MO 63110. E-mail kernm{at}slu.edu

Key Words: Editorials • receptors, adrenergic, alpha • ventricles

Understanding the role of -adrenergic receptors in the relationship between myocardial ischemia and left ventricular functional impairment is difficult and substantially more complex than simply producing a reduction in myocardial supply relative to the demand. Traditionally and in an oversimplified manner, ₁-adrenergic and postsynaptic adrenergic receptors are considered equivalent and mediate vasoconstriction. ₂-Adrenergic and presynaptic adrenergic receptors likewise are thought to be identical and mediate inhibition of sympathetic neural terminal release of norepinephrine. Further subtypes of ₁-,₂-adrenergic receptor subtype classifications (_1A, _1E, _2A, etc) exist but remain predominantly theoretical. Under normal conditions, -adrenergic vasoconstriction regulates metabolically induced coronary vasodilation to match oxygen supply to myocardial demand.¹ Under ischemic conditions, -adrenergic receptor stimulation may produce excess oxyradical production and calcium overload and release endothelial factors,^{2 3} theoretically and paradoxically potentiating myocardial ischemia. As clinicians, the difficulty in our understanding arises because of the many different experimental models and available -adrenergic receptor agonists and antagonists (Table 1). Heusch⁴ expertly identifies the controversial aspects of -adrenergic receptor activation, especially under conditions of ischemia, when this generally minor mediator becomes powerful enough to limit coronary blood flow when coronary vasodilatory reserve becomes exhausted. The potentially conflicting -adrenergic receptor responses can be inferred, in part, by response variances among anatomic locations (Table 2).

View this table: [in this window] [in a new window]   Table 1. Classification of -Adrenergic Receptor Subtypes in the Heart

View this table: [in this window] [in a new window]   Table 2. -Adrenergic Receptors and Left Ventricular Function

Additional complexity is added in conditions under which brief periods of myocardial ischemia, not resulting in myonecrosis, may be followed by longer-lasting contractile impairment and diminished regional blood flow or myocardial "stunning."^{5 6 7} Controversy exists as to the exact mechanisms responsible for producing left ventricular dysfunction during transient coronary flow impairment, but coronary artery vasoconstriction is frequently implicated, especially after endoluminal enlargement with angioplasty.⁸ This vasoconstrictor response may be delayed and persist beyond restoration of normal coronary flow⁹ and appears to be mediated, in part, by -adrenergic mechanisms related to mechanical stretching and stimulation of coronary mechanoreceptors of the dilated coronary artery.^{10 11} Intracoronary sympathetic blocking agents can counteract reduction in coronary vasoconstriction and the increased coronary resistance.¹²

Gregorini and colleagues^{12 13} have extended theoretical postulates and experimental observations to patients through a series of sophisticated clinical studies. In serial examinations of coronary vasomotion in 45 patients undergoing coronary angioplasty, Gregorini et al¹³ observed significant vasoconstriction in both the treated and control arteries that occurred 30 minutes after angioplasty. The vasomotor effects of - and ß-adrenergic receptor blockade with phentolamine, yohimbine, propranolol, propranolol followed by phentolamine, and bretylium were then compared. Arterial stretching and ischemia caused by angioplasty induced ₁-adrenergically mediated vasoconstriction that overwhelmed any ß-mediated vasodilatation. Simultaneous - and ß-blockade revealed a predominant peripheral ß-mediated vasodilatation. Vasoconstriction of the control vessel, not branching from the mechanically stimulated coronary artery, also provided strong evidence of neural sympathetic vasoconstrictor reflexes ("cross talk") among the coronary arteries.¹¹

In this issue of Circulation, Gregorini et al¹⁴ continue their advance on the role of the -adrenergic nervous system in the recovery of myocardial perfusion and function in ischemic patients, now in the setting of acute myocardial infarction. To test their hypotheses, they examined results in 40 patients 24 hours after thrombolysis and stenting during acute myocardial infarction. As in their previous studies,^{12 13} left ventricular function, as well as proximal coronary artery blood flow velocity, was assessed quantitatively by transesophageal echocardiography immediately before and after stenting and again 15 minutes later. Ten patients received phentolamine 12 µg/kg, 10 received urapidil 600 µg/kg IV (a selective ₁-blocker with central serotonergic effect without tachycardia or vasodilation), 10 received saline, and 10 patients pretreated with ß-blockers received urapidil 10 mg IC.

After stenting, both left ventricular function (percent fractional shortening) and angiographically estimated coronary blood flow (both velocity and by TIMI frame count) increased. However, these favorable effects were short-lived. Regional thickening deteriorated within 15 minutes in both the infarct-dependent and non–infarct-dependent myocardium, and TIMI frame count increased (ie, coronary blood flow decreased) to the values before angioplasty. In patients given -blockade (phentolamine and urapidil), left ventricular function was maintained with the increase in angiographic blood flow. Interestingly, these responses were attenuated in patients pretreated with ß-blockade. These data indicate that -adrenergic vasoconstriction mediates diffuse left ventricular contractile dysfunction, supporting the hypothesis that neural mechanisms, especially those mediated by -adrenergic receptors, contribute to left ventricular dysfunction despite restored coronary flow through a widely patent coronary lumen.

After successful thrombolysis for acute myocardial infarction, myocardial and coronary blood flow should, in theory, improve the microperfusion status and facilitate left ventricular contractile recovery. In many instances, this is the case. However, it has been amply demonstrated that infarct artery patency is not equal to reperfusion and that angiographic patency may overestimate the success of thrombolysis.¹⁵

Persistent contractile dysfunction after successful reperfusion therapy for myocardial infarction may be due to irreversible myocardial necrosis, reversible myocardial stunning, and/or microcirculatory perfusion abnormalities. Which of these mechanisms also involve the adrenergic control remains incompletely understood. The model used in the present study by Gregorini et al¹⁴ provides insight via the 3 different approaches to the responsible mechanisms for abnormal flow/functional sequelae after acute myocardial infarction. Because myocardial perfusion is purportedly restored by thrombolysis when the epicardial stenosis is also eliminated by an intracoronary stent, the effect of an adrenergic blocker on the microcirculatory perfusion and its associated influence on left ventricular dysfunction can be dissected. The use of stenting for this investigation is important. Unlike the unpredictable vessel responses after an angioplasty, nearly complete lumen enlargement can be expected with stenting, a method well suited to exclude the large-vessel resistance from the experimental variables. In this way and in patients with acutely infarcted myocardium, it is clear that -blockade normalized coronary (TIMI) flow, attenuated coronary vasoconstriction, and ameliorated left ventricular function. These results, similarly reported by the same group after the transient ischemia of coronary angioplasty, are relevant to appreciating the time course of -adrenergic receptors on left ventricular dysfunction during acute and severe ischemia.

One of the more interesting observations in the present study was that in the postthrombolysis period, the non–infarct-related artery demonstrated a slow-flow phenomenon, indicating that microvascular disturbances extended to the unaffected territories. Whether this result is due to a diffuse atherosclerotic process or is a function of interarterial reflexes or cross talk is unknown. The non–infarct-related artery response may also reflect net neural interactions or may be secondary to global myocardial dysfunction with decreased cardiac output. Slowed coronary flow in the non–infarct-related artery has been described by Uren et al¹⁶ and in preliminary reports from laboratories working with TIMI frame-count methodologies. The slower non–infarct-related artery flow is also consistent with other observations of diffuse microvascular dysfunction, especially in collateral-dependent myocardium.¹⁷

Neural trigger mechanisms and cardiocardiac sympathetic reflexes result in -adrenergic vasoconstriction,^{10 11} an effect that could be eliminated by -adrenergic blockers. The investigators justifiably argue that merely getting the artery open mechanically by eliminating the flow-limiting stenosis does not preclude the occurrence of persistently impaired coronary blood flow due to increased -adrenergic tone at the epicardial and microvascular levels. This observation is in contradistinction to the opinion held that coronary stenting completely reduces poor distal runoff and normalizes coronary blood flow in nearly all circumstances.¹⁸

It is a tribute to the investigative capabilities of the Milan laboratory and their collaborating centers that such a detailed pharmacological study of human coronary reflexes could be performed. As with any complex clinical study of this type, certain aspects merit discussion, but the data certainly support their hypothesis and extend our appreciation of the role of -adrenergic blockade in this human model.

The common concerns arising from the examination of such data in complex clinical studies in humans are straightforward. Although the patients were not randomized, the reflex responses are consistent within and among similar studies both from the same and from different institutions. A randomized drug protocol would be desirable but limited by the pharmacokinetics of the study agents. In the setting of the acute phase of myocardial infarction, such an approach is impractical, to avoid a prolonged clinically necessary procedure. Limiting the preprocedural use of nitroglycerin in some patients would also be difficult in this setting. Moreover, because the primary objective was to understand postreperfusion dysfunction, the results would not be critically dependent on pretreatment nitrates, which, by the way, were used in the posttreatment standardization of coronary angiographic dimensions.

With regard to coronary blood flow methodologies, it is acknowledged that the TIMI frame count is not a precise measure of blood or flow velocity, because the angiographic edge rate of travel has a wide variation compared with direct flow measurements.¹⁹ Transesophageal echocardiography likewise does not provide an accurate assessment of poststenotic coronary flow, because measurements can be obtained only in the proximal segments of the left anterior descending coronary artery. The transesophageal echocardiographic method often precludes measurement of flow in the non–infarct-related vessel in the case of circumflex or right coronary artery and thus, although technically validated, may not provide data identical to those of direct multivessel intracoronary measurements.

Although relief of coronary flow obstruction by thrombolysis and stenting for acute myocardial infarction can ameliorate supply-side ischemia, immediate recovery of left ventricular dysfunction is not produced consistently. Both coronary conductance and microvascular resistance are influenced by -adrenergically mediated vasoconstrictor tone, a mechanism that influences global left ventricular dysfunction as an interrelated factor. From this work, adrenergic and more specifically -adrenergic receptor neural mechanisms appear to play more than a minor role in these phenomena both directly and by reflex (cross talk) interaction.

Whether the extension of these data to the clinical treatment of patients with the postinfarct slow perfusion syndrome would demonstrate benefit by -blockers cannot be answered in such a small patient subset. This study does provide important pilot data to consider control of the -adrenergic system as a potential therapeutic adjunct in the treatment of myocardial infarction. Studies such as those by Gregorini et al¹⁴ suggest promising potential therapeutic approaches to improving left ventricular function in patients with ischemic heart disease and acute myocardial infarction.

Acknowledgments

The author wishes to thank Donna Sander for preparation of the manuscript.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

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